Li D, Wang M, Cheng L, Spitz M R, Hittelman W N, Wei Q
Department of Clinical Investigations, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 1996 Aug 15;56(16):3638-41.
Given the same exposure, DNA adduct profiles can be considered as a phenotypic marker for carcinogen metabolism and DNA repair, which may reflect individual susceptibility to chemical carcinogenesis. Based on this notion, we have established a straightforward assay that measures induced DNA adducts in peripheral lymphocytes exposed in vitro to a model carcinogen, benzo(a)pyrene diol epoxide (BPDE) by 32P-postlabeling. To test the hypothesis that the levels of induced DNA adducts are a predictor for cancer risk, we conducted a pilot study of 21 lung cancer patients and 41 healthy frequency-matched controls. We found that the peripheral lymphocytes of cancer patients tended to accumulate higher levels of BPDE-DNA adducts than controls did (mean +/- SE of relative adduct labeling x 10(7) value; 59.6 +/- 12.0 versus 39.4 +/- 6.1 for cases and controls, respectively; P = 0.09). Using the tertile relative adduct labeling value of controls (10 adducts/10(7) nucleotides) as the cutoff point, 18 of 21 cases and 23 of 41 controls distributed above this level (odds ratio, 4.7; 95% confidence interval, 1.2-18.5). In logistic regression analysis, the level of induced adduct was an independent risk factor (odds ratio, 6.4; 95% confidence interval, 1.3-29.4) after adjustment for the potential confounding factors, i.e., age, sex, ethnicity, and smoking. Stratified analyses showed that greater differences in DNA adduct levels induced by BPDE between cases and controls were observed in individuals younger than 65 years and in nonsmokers. Despite the small sample size, the significant association between the level of BPDE-induced DNA adducts and risk for lung cancer suggests that this assay is a promising method for further investigations.
在相同暴露条件下，DNA加合物谱可被视为致癌物代谢和DNA修复的表型标志物，这可能反映个体对化学致癌作用的易感性。基于这一概念，我们建立了一种直接的检测方法，通过32P后标记法测量体外暴露于模型致癌物苯并(a)芘二醇环氧化物（BPDE）的外周血淋巴细胞中诱导产生的DNA加合物。为了检验诱导DNA加合物水平是癌症风险预测指标这一假设，我们对21例肺癌患者和41例频率匹配的健康对照进行了一项初步研究。我们发现，癌症患者外周血淋巴细胞中BPDE-DNA加合物的积累水平往往高于对照组（相对加合物标记的平均±标准误×10(7)值；病例组和对照组分别为59.6±12.0和39.4±6.1；P = 0.09）。以对照组的三分位数相对加合物标记值（10个加合物/10(7)个核苷酸）作为截断点，21例病例中有18例以及41例对照中有23例分布在此水平之上（比值比，4.7；95%置信区间，1.2 - 18.5）。在逻辑回归分析中，在对年龄、性别、种族和吸烟等潜在混杂因素进行调整后，诱导加合物水平是一个独立的风险因素（比值比，6.4；95%置信区间，1.3 - 29.4）。分层分析表明，在65岁以下个体和非吸烟者中，病例组和对照组之间由BPDE诱导的DNA加合物水平差异更大。尽管样本量较小，但BPDE诱导的DNA加合物水平与肺癌风险之间的显著关联表明，该检测方法是一种有前景的进一步研究方法。
